Process for the preparation of delta-3, 4-thiazolines



United States Patent 3,004,981 PROCESS FOR THE PREPARATION OFA-3,4-THIAZOLINES Friedrich Asinger, Langebruck, near Dresden, and MaxThiel and Herman Hauthal, Leuna, Germany, as-

signors to VEB Leuna-Werke Walter Ulbricht, Leuna, Germany No Drawing.Filed July 16, 1958, Ser. No. 748,802 Claims priority, applicationAustria Aug. 9, 1957 9 Claims. (Cl. 260-6065) This invention relates toa process for the preparation of A-3,4-thiazolines.

It is known that A-3,4-thiazolines are obtained when ammonia is allowedto react at room temperature with an equimolar mixture of anu-mercapto-aldehyde or a mercaptoketone and a keto group C=O) containingcompound (oxo compound). It has now been found that a-diketo-disulfidescan also be converted into A-3,4thiazo- This reaction is particularlyadvantageous, when the a-diketo-disulfide is more easily accessible thanthe corresponding a-mercaptoketone.

,The process of the present invention comprises causing a mixture of 1mole of an a-diketodisulfide with at least 2 moles of an oxo compound,e.g., an aldehyde or ketone, to react simultaneously at room temperaturewith H S and NH The H 8 and the NH are preferably employed in theproportion by volume of 1:1. In place of ammonia, the ammonium salts ofthe weaker acids can also be employed. The process can also be carriedout so that the mixture of oc-diketodisulfide and oxo compound arestirred for several hours with an aqueous ammonium sulfide solution.This process is represented by wherein R is an alkyl radical and R and Rare hydrogen or alkyl. When R R or R are alkyl radicals they may be thesame or diiferent alkyl radicals and may be lower or higher alky-lstraight chain or branched chain alkyl. Among the alkyl radicals thatare represented by R R and R are: methyl; ethyl; n-propyl; iso-propyl;n-butyl; iso-butyl; tert-butyl.

R R and R in Formula 2 may also represent a wide variety of aryl,aralkyl and cycloalkyl radicals. Among the representative radicals arethe following: cyclopentyl, cyclohexyl, phenyl and benzyl.

A large variety of aldehydes and ketones may be used in accordance withthe process of the present invention. Thus, for example, among thealiphatic and alicyclic aldehydes may be mentioned: acetaldehyde,propionaldehyde, n-butyraldehyde, n-valeraldehyde,trimethylacetaldehyde, cyclohexanealdehyde. Among the substitutedaliphatic ICC may be used in accordance with the process of the presentinvention. Thus, for example, ketones of. formula o=o R5 wherein R and Rmay be the same or different alkyl group. In this case R 'and R may belower or higher alkyl chains and may be straight chain or branchedchain. R and R may also be joined to form a cycloalkyl radical.

Among the aliphatic ketones that are useful may be mentioned acetone,methylethylketone, methyl-n-propylketone, diethyl ketone andmethylisobutyl ketone.

Among the alicyclic ketones that may be used in accordance with thisinvention may be mentioned: cyclopentanone and cyclohexanone.

In a similar manner alkyl-aryl ketones may be used in the process of thepresent invention. These include, e.g., methyl benzyl ketone. a

As in the case of the aldehydes various substituted ketones may beemployed in the process of this invention. The functional groupsconstituting the substituents are quite varied. Thus, among the hydroxyketones that have been employed is included propioin(4-hydroxy-3-hexanone).

Another class of substituted ketones that may be used in accordance withthe present invention are the keto esters. By way of illustrationw-acetylvaleric acid esters may be mentioned.

The reaction is accelerated by means of small quantities of Water; inertsolvents such as alcohols, ethers or hydrocarbons have substantially noinfluence on the reaction.

. By the quick introduction of the gas mixture, the tem- Example 1 206g. of bis(buta n-3one-2-yl)-disulfide and 144 g. of butanone aresaturated with H 8 while being stirred. The introduction of NH is thenbegun and the velocity of the two streams of gas (NH and H 8) aremaintained about equal. The reaction is completed after approximately 4hours. The reaction mixture consists of two phases. The non-aqueousphase is taken up in ether or another waterinsoluble organic solvent,while the aqueous ammonium sulfide containing layer is discarded. Thesolution is dried and concentrated. The residue yields on distilling 270g. of 2,4,5-trimethyl-2-ethyl-A-3,4-thiazoline of B.P. mm Hg 63-64 C.of-theory).

' Example 2 234 g. of bis-(pentan-3-one-2-yl)-disulfide and 196 g. ofcyclohexanone are treated with NH and H 8 and worked up as described inExample 1. One obtains 360 g. of2,Z-pentamethylene-4-ethyl-5-methyl-A-3,4-thiazoline of B.P. m Hg 102C.(91% of theory).

Example 3 H 8 is fed into a mixture of 39 g. of bis(pentan-3-one-2- yl)disulfide, 40 g. diethyl ketone, cc. of methanol and 30 g. of ammoniumcarbonate for several hours. The reaction mixture is then extracted withether. The distillation of the ether extract yields 47 g. of2,2,4-triethyl- -methyl-A-3,4-thiazoline of B.P. mm Hg 7073 C. (76% oftheory).

. Example 4 45 g. bis-(pentan-3-one-2-yl)-disulfide, 150 g.diethylketone and 200 cc. of a colorless aqueous ammonium sulfidesolution containing about 90 g. of S per liter is vigorously stirred for8 hours, whereby the reaction mixture assumed a reddish yellow color.The organic layer is then separated, washed with water, dried anddistilled. One obtains 50 g. of 2,2,4 triethyl 5 methyl-A-SA- thiazolineof B.P. mm Hg 70-73 C. (71% of theoretical yield).

. Examplefi A mixture of 90 g. bis-acetonyl-disulfide and 58 g. ofpropionaldehyde is treated equal quantities of NH; and H Sas describedin' Example 1.

The distillation of the residue obtained after'evaporation of thepetroleum ether gives 116 g. of 2-ethyl-4-methy1- A- 3,4-thiaz'oline ofB.P. m 57-59 (90% of theory).

Ammonia and H 8 at a 1:1 ratio are fed into a mixture of 250 g4,9-dioxo-6,7-dithia-5,S-diethyldodecane and 174 g. propionaldehyde. Theprocedure of Example 1 is followed in wonking up the reaction mixturewhich yields 315 g. 2,5-diethy1-4-n-propyl-thiazoline-A-3,4 having aB.P. of 7577 C. at 1 mm. The picrate of the compound has a melting pointof 97-98 C. The yield corresponds to 85% of the theoretical valuef V 7Example 8 145 g. 3,8 dioxo-S,6-dithia-2,4,4,7,7 ,9 hexamethyldecane aremixed with 88 g. acetaldehyde and are treated with NH; and H S asdescribed above. The reaction product is worked up in the mannerdescribed in Example 1. 111 g. (65% of theoretical yield) of2,5,5-trimethyl-4-isopropyl-thiazoline-A-3,4 are obtained and have aboiling mm. Hg. The picrate melts at point of 63-6 4 C. at 8 "Example 9Ammonia and H 8 are fed for 8 hours into a mixture of 151' g. diphenacyldisulfide, 60 g. propionaldehyde, and 500 ml.. ether. The ether solutionis separated from the aqueous polysulfide solution, filtered, washedwith water, dried over calcinedsodium sulfate, and evaporated todryness. The residue is recrystallized from methanol. 143 g. (76% oftheoretical yield) of 2-ethyl-4-phenylthiazoline-A-3,4 of M.P."5051 C.is obtained.

, 165 g. 2,7-dioxo-4,5-dithia-3IG-diphenyIQctane' and 8 '116 v Thereaction ture is worked up by extraction with petroleum ether.

. B.P. 162-163 C. are obtained.

H S as described in Example 1 above.

l; action product is worked up as indicated there.

Example 11 A mixture of 130 g. bis-a-cyclohexanonyl disulfide and 100 g.cyclohexanone is treated with H S and NH as indicated in Example 1. Thereaction mixture is taken up in ether, the ether solution is dried andevaporated. The crystalline residue is recrystallized from di-n-propylether and 188 g. (90% of theoretical yield) of 2,2=pentamethylene-4,5-tetramethylene-thiazoline A 3,4 are obtained. Themelting point of the compound is 83 C.

V *Example 79 g. bis-lacetylcyclohexyl disulfidean 60 g. diethyl ketoneare simultaneously treated with NH and H 8 and the reaction product isworked up as described.

in Example 1. 89 g. (81% of theoretical yield) of 2,2diethyl-4-methyl-5,5-pentamethylene-thiazoline A 3,4 of

The picrate has a meltingpoint of 134-135SC." Example 13 79gbis-hexahydrobenzoylmethyl-disulfide and g.

cyclohex'anone are treated simultaneously with NH and 103 g. (87% oftheoretical yield) of 2,2-pentamethylene-4-cyclohexylthiazoline-A-3,4are obtained, having aboiling point at 4 mm. Hg. of 166168 C; and amelting point of 34 C. The picrate melts at C1 7 2 i Example l4 7 v 131g. 3,8-dioxo-5,6-dithia 2,2,9,9-tetramethyldecane and 100 g.propionaldehyde are treated with NH and H S at a ratio of 1:1 asdescribed in Example 1, and the re- 156 g. (91% 1. of theoretical yield)of 2-ethyl-4-tert-butyl-thiazoline-*A-'3,4 0f" B.P.' 86-87 C. picratemelts at 128.5 C.

Example 15 83 g. bis-phenylacetonyl-disulfide, g. phenylacetone and 50m1. methanol and are mixed and saturated with H 5. H 8 and NH are fed tothe mixture at a volume ratio of 1:1 until the temperature first risesto 5070 C. and then returns to room temperature. The reaction product isdiluted with water and is extracted with ether. The extract is washedwith water and dried. It is then evaporated and the residue is distilledin a vacuum. 119. 'g. (85% of theoretical yield) of 2-methyl-2,4-dibenzyl-thiazoline-A-3'A is obtained and has] a B.P. of anM.P. of 67-68v C. The picrate melts at C.

r Example 16 A mixture of 117 g. bis-pentan-3-on-2-yl disulfide and 136g. propioin is diluted with methanol as indicated in Example 15 and isthen treated With NI-I and H 5. The reaction product is worked up toyield g. (71% of theoretical yield) of2-(a-hydroxy-n-propyl)-2,4-diethyl- 5-methy1-thiazoline-A-3,4.

Example 17 A mixtureof 117 g.'bis-pentan-3-on-2-yl disulfideand 72 g.visotmtyraldehyde are treated with NH and H 8 as indicated in Example 1.145 g. (80% of theoretical yield) ofZ-isopropyl-4-ethyl-S-methyl-thiazoline-A-3,4 of

3 B.P. 88-90.":C. are obtained. The picrate melts at 117- Example 18.

A mixture of 117 g. bis-pcntan-3-on-2-yl disulfide and 120 g.hexahydrobenzaldehyde are treated with NH and H 8 as described inExample 1. 202 g. (96% of theoretical yield) of2-cyclohexyl-4-ethyl-S-methyl-thiazoline- A-3,4 of B.P. 100-1 10 C. areobtained. The picrate Example 1 9 are obtained. The

A mixture of 118 g. bis-pentan-3-on-2-yl disulfide witli 144 g.fi-formylbutyric acidethyl ester is mined, with 2 ml. water' 'andtreated With NI-Ijand ins-as described in Exampl l, TheIGaCfiQlLPlYOdllCfiiS.WQIkd upasindicated above and ,190 g. (78%, ;of;theoretica1-yie1d),-of 2 (1 -inethy1 2' -carbethoxyethyl) 4 ethyl-15 mshrlhia ins-Afie ar tai ed. havi g -Pa of 121-123c. '1

- v Ex mpl 1. .1,

A mixture of 88 g. ethoxyacetaldehyde and 1l7g. bispentan-3-on-2-yldisulfide is mixed with 250 ml. water and is then treated with NH and H8 as in Example 1 with vigorous agitation. 141 g. (75% of theoreticalyield) of Z-ethoxymethyl-4-ethyl-S-methyl-thiazoline-A- 3,4 of B.P.114116 C. are obtained.

Example 22 115 g. bis-a-cyclopentanonyl disulfide and 100 g.cyclopentanone are treated with NH; and H 8 as described above. From thereaction product 125 g. (69% of theoretical yield) of2,2-tetramethylene-4,S-trimethylene-thiazoline-A-3,4 are obtained andhave a B.P 0,2 of 93 C.

The a,a'-diketodisulfides employed in the above examples may be preparedfrom the corresponding a-mercapto ketones. The a-mercaptoketones in turnmay be prepared either from the a-halogen ketones by reaction with Na SHaccording to O. Hromatka et al. (Mh. Chem. 78, 29, 1947, 85, 830, 1954)and T. Bacchetti et a1. (Gazz. chim. ital. 83, 655, 1953; 83, 824, 1953;83, 1031, 1953) or according to the co-pending US. application Ser. No.615,227. The conversion of the a-mercaptoketones into the disulfides isaccomplished with the common oxidizing agents as has been described inconnection with simple mercaptanes (see Houben-Weyl, Methoden der organ.Chernie, volume IX, 55, Georg Thieme .Verlag, 1955) and F. H. McMillanand J. -A. King, Journ. Amer. Chem. Soc. 70,4143, 1950).

The preparation of the a,a'-diketodisulfides is illustrated by thefollowing two examples.

Example 23 208 g. of ammonium persulfate dissolved in 250 cubiccentimeters of water are added dropwise and under stirring at atemperature of 10 C. to a solution containing 250 g. ofa-mercapto-diisopropylketone in 68 g. of NaOH and 700 cubic centimetersof water. The reaction mixture thus obtained is stirred for a further 30minutes whereafter extraction with ether is performed. Distillation ofthe ether residue yields at a RF. 2 mm. Hg of 132-l34 C., 206 g. of3,8-dioxo-5,6-dithia-2,4,4,7,7,9- hexamethyldecane (83% of the theory).

Example 24 96 g. of finely comminuted sulfur are added to 708 g. ofZ-mercapto-pentanone-(3). Upon stirring a vigorous H development takesplace after a short time which persists for 2 to 4 hours. (If desiredsmall amounts of amine may be added as catalyst.) When the sulfur hasbeen consumed, the reaction mixture may immediately be distilled invacuo. 580 g. of bis-(pentane-S-on-Z-yl) disulfide (see Examples 2-4, 6,and 16-20) at a B.P. 5 mm. Hg of 146-149 C., which correspond to 83% oftheory, are obtained.

The thiazoline-A-3,4 obtained by the inventive reaction exhibitconsiderable physiological action and may thus be used in the synthesisof therapeutic agents. They constitute valuable intermediates and finalproducts for the pharmaceutical industry. Further, they may be used formany other purposes, as, for example, as agents for comclaims.

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and aging. v

While the invention has been described with particular reference tospecific embodiments, it is to 'be understood that it is not limitedthereto, but is to be construed broadly and restricted solely by thescope of the appended What is claimed ist v I i H H I i I. A process forthe preparation of A-3,4-thiazolines,

' which comprises reacting a .mixture of H 8 and NH3 with a mixture ofan a,a'-dike todisulfide of the general emal and an oxo compound of thegeneral formula wherein R R and R represent members selected from thegroup consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylformed by a combination of the group R and one of the groups R and R andcycloalkyl formed by a combination of R and R and R and R are membersselected from the group consisting of H, alkyl, alkyl containingsubstitutents inert in the reaction, aralkyl, cycloalkyl and cycloalkylhaving from 5 to '6 carbon atoms formed by a combination of R and R saidmembers being free from groups which would interfere with the reaction.

2. The process as claimed in claim 1, wherein the u,a'-diketodisulfideand the oxo-compound are employed in the molar ratio of 1:2.

3. The process as claimed in claim 2, wherein the NH, and H S arepresent in the ratio of 1 part of NH to 1 part of H S by volume.

4. A process as claimed in claim 3, wherein the reaction is carried outat a temperature not exceeding 40 C.

5. A process as claimed in claim 3, wherein the reaction is carried outat ordinary room temperatures.

6. A process as claimed in claim 5, wherein the reaction is carried outin the presence of an inert solvent.

7. A process as claimed in claim 5, wherein the reaction is carried outin the presence of a small quantity of water.

8. A process for the preparation of A-3,4-thiazolines, which comprisesreacting a mixture of H 8 and an ammonium salt of a weak acid with amixture of an oz,ix'- diketodisulfide of the general formula and an oxocompound of the general formula o=o Rf wherein R R and R representmembers selected from the group consisting of H, alkyl, aryl, aralkyl,cycloalkyl, cycloalkyl formed by a combination of the group R and one ofthe groups R and R and cycloalkyl formed by a combination of R and R andR and R are members selected from the group consisting of H, alkyl,alkyl containing substituents inert in the reaction, aralkyl, cycloalkyland cycloalkyl having from 5 to 6 carbon atoms formed by the combinationof R and R said members being free from groups which would interferewith the reaction.

9. A process for the preparation of A-3,4-thiazolines,

I R; 7 R3 r R1oo- 3 -s-s oo m 5 and an 0X0 compound of the generalformula wherein R R and R represent members selected from the groupconsisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkyl formed bya combination of the group R and 15 one of the groups R: and R andcycloalkyl formed by a combination of R andR and R; and R are membersselected from the group consisting of H, alkyl, alkyl containingsubstituents inert in the'reactiomaralkyl, cycloalkyl and cyeloalkylhaving from 5 to '6 carbon atoms formed by the combination of R and Rsaid members reaction.

References Cited in the file of this patent Asinger: Angew. Chem, vol.68, p. 413 (-1956). Asinger et al.: Liebigs Ann., vol. 9 602, pp. 37-49(1957). V

Asinger (1957).

Asinger (.1958).

et al.: Liebigs Ann., vol. 610, pp'. 3349 et 211.: Chem; Abstracts, vol.'52, col. 6395

1. A PROCESS FOR THE PREPARATION OF $-3,4-THIAZOLINES, WHICH COMPRISES REACTING A MIXTURE OF H2S AND NH3 WITH A MIXTURE OF AN A,A''-DIKETODISULFIDE OF THE GENERAL FORMULA 